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POSTERS predict in the very early period subsequent individual response. Starting from the clinical experience in humans that subcutaneous metastases may rapidly change consistency under sorafenib and that elastosonography a new ultrasound based technique allows assessment of tissue stiffness, we investigated the role of elastonography in the very early prediction of tumor response to sorafenib in a HCC animal model. Methods: HCC (Huh7 cells) subcutaneous xenografting in mice was utilized. Mice were randomized to vehicle or treatment with sorafenib when tumor size was 5–10 mm. Elastosonography (Mylab 70XVG, Esaote, Genova, Italy) of the whole tumor mass on a transversal plane with a 10 MHz linear transducer was performed at different time points from treatment start (day 0, +2, +4, +7 and +14) until mice were sacrified (day +14), with the operator blind to treatment. In order to overcome variability in absolute elasticity measurement when assessing changes over time, values were expressed in arbitrary units as relative stiffness of the tumor tissue in comparison to the stiffness of a standard reference standoff pad lying on the skin over the tumor. Results: Sor-treated mice showed a smaller tumor size increase at day +14 in comparison to vehicle-treated (tumor volume increase +192.76% vs +747.56%, p = 0.06). Among Sor-treated tumors, 6 mice showed a better response to treatment than the other 4 (increase in volume +177% vs +553%, p = 0.011). At day +2, median tumor elasticity increased in Sor-treated group (+6.69%, range −30.17 to +58.51%), while decreased in the vehicle group (−3.19%, range −53.32 to +37.94%) leading to a significant difference in absolute values (p = 0.034). From this time point onward, elasticity decreased in both groups, with similar speed over time, not being statistically different anymore. In Sor-treated mice all 6 best responders at day 14 showed an increase in elasticity at day +2 (ranging from +3.30% to +58.51%) in comparison to baseline, whereas 3 of the 4 poorer responders showed a decrease. Conclusions: Elastosonography appears a promising non-invasive new technique for the early prediction of HCC tumor response to sorafenib. 250 RND3/RHO-E IS DOWN-REGULATED IN HEPATOCELLULAR CARCINOMA AND INVOLVED IN CELLULAR INVASION F. Grise1 , S. Sena1 , A. Bidaud-Meynard1 , J. Baud2 , N. DugotSenant1 , C. Staedel2 , P. Bouliac-Sage1,3 , J. Zucman-Rossi4 , J. Rosenbaum1 , V. Moreau1 . 1 Inserm U889/Universit´e Bordeaux 2, 2 Inserm U869/Universit´e Bordeaux 2, 3 Groupement des Sp´ecialit´es Digestives/CHU, Bordeaux, 4 Inserm U674, Paris, France E-mail: [email protected] Background: Hepatocellular carcinoma (HCC) is the main primary malignancy of the liver and one of the most common and aggressive cancer worldwide, causing 500,000 to 1 million deaths annually. HCC diagnosis is often done at advanced stages of the disease when curative solutions, mostly based on surgery, can no more be proposed. Therefore the development of new molecular targets for therapy, drugs and treatment strategies are needed. From micro-array data analysis, we noticed the significant downregulation of Rnd3 expression in HCC. Rnd3, also called RhoE, belongs to the RhoGTPase family and is atypical, since in contrast to other GTPases, it is always in its active GTP-bound form. Here, we address the role of Rnd3 in HCC development. Methods: We used quantitative real time PCR, immunohistochemistry and western-blot analyses to confirm Rnd3 down-regulation in human tumors and HCC cell lines. We used RNA interference to knockdown Rnd3 in cultured tumor hepatocytes. Actin cytoskeleton and cell-cell junctions were analyzed by immunofluorescence. In vitro invasive phenotype was tested by Boyden chamber assay. Epithelio-mesenchymal transition (EMT) markers were quantified using either qRT-PCR or western-blot.
Results: The down-regulation of Rnd3 in HCC was confirmed by measuring its expression in 100 tumors by qRT-PCR. Moreover, we confirmed this down-expression at the protein level. Based on these results, we aimed at better characterizing the role of Rnd3 in hepatic carcinogenesis. To this end, we analyzed the impact of Rnd3 knockdown in cultured tumor hepatocytes. We found that downregulation of Rnd3 expression induced actin cytoskeleton and cellcell junction alteration. In addition, knockdown of Rnd3 increased cell invasion and led to an EMT, confirmed by the down-regulation of E-Cadherin and the up-regulation of ZEB1/2 EMT factors expression. We further analyzed the pathways involved in Rnd3 knockdown-induced invasion and found that tumor hepatocyte invasion occurred in an MMP-independent, and Rac1- and Cdc42dependent manner. Conclusion: Rnd3 is down-regulated in HCC. Our results showed that this down-regulation participates in the establishment of a mesenchymal phenotype to promote invasion of liver tumor cells. 251 EXPRESSION OF TRICELLULIN, A RECENTLY IDENTIFIED TIGHT JUNCTION PROTEIN IN NORMAL LIVER AND IN PRIMARY LIVER CANCERS ´ Somoracz, A. ´ A. Korompay, A. Patonai, B. Erdelyi-Belle, ´ P. Torzs ¨ ok, ¨ G. Lotz, Z. Schaff, A. Kiss. 2nd Department of Pathology, Semmelweis University, Budapest, Hungary E-mail: [email protected] Background: Tight junction (TJ) proteins – such as occludin and claudins (CLDNs) – play an important role in carcinogenesis. Tricellulin (TRIC) is a newly described transmembrane TJ protein localized mainly at the sites where three epithelial cells meet, but also identified in bicellular TJs. The implication of CLDNs (e.g. CLDNs-1, -4, -10) has already been demonstrated in liver carcinogenesis, however, no data exist about the possible role of tricellulin in primary malignancies of the liver. The aim of this study was to characterize TRIC expression of normal liver, as well as of primary liver cancers, including hepatocellular (HCC) and cholangiocellular (CCC) carcinomas. Materials and Methods: TRIC expressions in 10 non-tumorous, non-fibrotic liver tissue specimens, as well as 20 HCC and 20 intrahepatic CCC samples were investigated by immunohistochemistry, immunofluorescence, and Western-blot analysis. The immunohistochemical reactions were evaluated both semiquantitatively and by digital morphometry. Results: TRIC was detected at the apical pole of normal hepatocytes (HC), and showed ’railway line-like’ pattern between two HCs. In normal bile ducts (BD), TRIC was localized at the luminal surface of the cells and gave strong spotty immunostaining. TRIC expression was decreased in HCCs as compared with normal liver tissue. On the other hand, the spotty immunoreaction was more pronounced in well-differentiated tumorous glands of CCCs than in normal biliary ducts, however, poorly differentiated tumor cells showed no immunopositivity. According to Western blot analysis, specific bands at 64 kDa could be detected in normal liver samples and tumors. In addition, a larger product (80 kDa) was also identified in some HCC and CCC cases. Conclusions: This is the first report to describe the presence of TRIC in normal human liver and in primary hepatic malignancies. Since TRIC could be detected in well differentiated tumor cells and was absent from poorly differentiated areas, a correlation between the loss of its expression and tumor progression might be hypothesized. This study was supported by grant # OTKA 75468.
Journal of Hepatology 2011 vol. 54 S61–S208